1. Field of the Invention
This invention relates to a method for treating inflammatory bowel disease by administering histamine H.sub.3 receptor agonists.
2. Summary of the Related Art
Histamine (2-(4-imidazolyl)ethylamine) is found naturally in most tissues of both plants and animals. It exerts its biologic actions by combining with cellular receptors located in or on the surface membrane. There are at least three distinct types of receptors: H.sub.1, H.sub.2, and H.sub.3. Some of the known effects of histamine are exerted on smooth muscle and cardiac muscle, on endothelial and nerve cells, and on the secretory cells of the stomach.
The histamine H.sub.3 receptor is the latest receptor to have been identified (e.g., Arrang et al., Nature, 327:117 (1987) and Vander Werf et al., Trends Pharmacol. Sci., 10:159 (1989)). Stimulation of this receptor with H.sub.3 receptor agonists has been employed to treat a variety of conditions such as anxiety, allergy, gastrointestinal ulcers, cardiovascular diseases, central nervous system disorders, psychiatric disorders, sexual dysfunction, and sleep disorders. The majority of the compounds synthesized for this purpose are derivatives of histamines, in other words, 2-substituted imidazoles.
More recently, H.sub.3 -receptor agonists have been used in the treatment of inflammation. Generally, various 2-substituted imidazoles have been synthesized to treat inflammation (e.g., Khan et al., International Publication No. WO 96/40126 and Aslanian et al., U.S. Pat. No. 5,463,074). The treatment of inflammation of the bronchi has also been specifically disclosed (Schwarz et al., U.S. Pat. No. 5,321,039).
The treatment of inflammatory bowel disease (IBD), however, has not been addressed with the use of H.sub.3 -receptor agonists. The principal drugs used in the treatment of (IBD) are corticosteroids and other immunosuppressive agents, as well as sulfasalazine. IBD, however, is a special type of inflammatory process whose response to anti-inflammatory compounds developed for other indications is unpredictable. Nonsteroidal anti-inflammatory drugs (NSAIDs) for instance, are potent anti-inflammatory compounds useful for treating inflammatory processes in several organs and tissues. However, many NSAIDs are ineffective in the treatment of IBD and can actually exacerbate experimental colitis in animals and activate quiescent inflammatory bowel disease in humans (e.g., Wallace et al., Gastroenterology, 102:18-27 (1992); Kaufmann et al., Annals of Internal Medicine, 107:513-516 (1987)). Therefore, it cannot be extrapolated that anti-inflammatory drugs developed to treat inflammation in other organs and tissue will also have a beneficial effect in treating IBD.
Because there are many mediators present in an inflammatory response, and inflammation in different areas have different mechanisms of action, it is difficult to predict what the correct therapy is for any specific inflammatory response. Compounds useful for treating one type of inflammatory disease or state are not necessarily useful for treating others. Therefore, the use of histamine H.sub.3 -receptor agonists for the treatment of IBD is a necessary and novel approach in this area of inflammation.